Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

Mathews, Stephanie; Feng, Dechun; Maricic, Igor; Ju, Changqing; Kumar, Vipin; Gao, Bin

doi:10.1038/cmi.2015.06

Cited by 74 publications

(67 citation statements)

References 39 publications

(65 reference statements)

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“…Several reports have recently indicated that the activation of NKT cells are involved in chronic-plus-binge ethanol-induced liver injury and inflammation [25, 28, 29]. A previous study reported that aging is associated with increased NKT cell function as demonstrated by markedly increased liver injury in middle-aged mice after α-Galcer injection [30], suggesting that hepatic NKT cells are more active in middle-aged mice than in young mice.…”

Section: Resultsmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

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130

107

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Background and Aims Aging is known to exacerbate the progression of alcoholic liver disease (ALD), but the underlying mechanisms remain obscure. Methods C57BL/6 mice were subjected to short-term (10-days) ethanol-plus-one binge or long- term (8-weeks) ethanol-plus-multiple binges of ethanol. Liver injury and fibrosis were determined. Hepatic stellate cells (HSCs) were isolated and used in in vitro studies. Results Compared to young (8–12 weeks) mice, middle-aged (12–14 months) and old (>16 months) mice were more susceptible to liver injury, inflammation, and oxidative stress induced by short-term-plus-one binge or long-term-plus-multiple binges of ethanol feeding. Long-term-plus- multiple binges of ethanol feeding induced greater liver fibrosis in middle-aged mice than that in young mice. Hepatic expression of Sirtuin 1 (SIRT1) protein was downregulated in the middle-aged mice compared to young mice. Restoration of SIRT1 expression via the administration of adenovirus-SIRT1 vector ameliorated short-term-plus-binge ethanol-induced liver injury and fibrosis in middle-aged mice. HSCs isolated from middle-aged mice expressed lower levels of SIRT1 protein and were more susceptible to spontaneous activation in in vitro culture than those from young mice. Overexpression of SIRT1 reduced activation of HSCs from middle-aged mice in vitro with downregulation of PDGFR-α and c-Myc, while deletion of SIRT1 activated HSCs isolated from young mice in vitro. Finally, HSC-specific SIRT1 knockout mice were more susceptible to short-term-plus-binge ethanol-induced liver fibrosis with upregulation of PDGFR-α expression. Conclusions Aging exacerbates ALD in mice through the downregulation of SIRT1 in hepatocytes and HSCs. Activation of SIRT1 may serve as a novel target for the treatment of ALD.

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Section: Resultsmentioning

confidence: 99%

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Ramírez

Yin

et al. 2017

Journal of Hepatology

Self Cite

130

107

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“…In addition to causing hepatocyte death, NKT cells also promote cholangiocyte death via secreting hedgehog ligands and osteopontin in methionine choline-deficient diet inducing NASH mouse model [25]. In alcohol-induced liver injury mouse model, type I, but not type II, NKT cells are activated, leading to NKT cell-mediated neutrophil (Gr-1 high CD11b + ) recruitment into the liver and hepatocellular injury [53,54]. Recent studies showed that alcohol-induced NLRP3 activation can recruit and activate hepatic iNKT cells, thereby causing alcoholic liver injury [55].…”

Section: Nkt Cells In Liver Injury and Inflammationmentioning

confidence: 99%

Natural killer T cells in liver injury, inflammation and cancer

Wang

Yin

2015

Expert Review of Gastroenterology & Hepatology

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The liver is an organ that has the largest amount of natural killer T(NKT) cells, which play critical roles in the pathogenesis of liver diseases. In this article, the authors summarize recent findings about the roles of NKT cells in liver injury, inflammation, fibrosis, regeneration and cancer. In brief, NKT cells accelerate liver injury by producing pro-inflammatory cytokines and directly killing hepatocytes. NKT cells are involved in complex roles in liver fibrogenesis. For instance, NKT cells inhibit liver fibrosis via suppressing hepatic stellate cell activation and can also promote liver fibrosis via enhancing liver inflammation and injury. Inactivated or weakly activated NKT cells play a minimal role in controlling liver regeneration, whilst activated NKT cells have an inhibitory effect on liver regeneration. In liver cancer, NKT cells play both pro-tumor and anti-tumor roles in controlling tumor progress.

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“…However, NK cells also contribute to neutrophil infiltration of liver in mouse models of ALD. 103 Early-phase clinical trials are being designed to alter activities of NK cells in patients with ALD.…”

Section: Adaptive Immune Responsesmentioning

confidence: 99%

Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes

et al. 2016

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Alcoholic liver disease (ALD) develops in approximately 20% of alcoholics, with a higher prevalence in females. ALD progression is marked by fatty liver and hepatocyte necrosis, as well as apoptosis, inflammation, regenerating nodules, fibrosis, and cirrhosis 1. ALD develops via a complex process involving parenchymal and non-parenchymal cells, as well as recruitment of other cell types to the liver in response to damage and inflammation. Hepatocytes are damaged by ethanol, via generation of reactive oxygen species and induction of endoplasmic reticulum stress and mitochondrial dysfunction. Hepatocyte cell death via apoptosis and necrosis are markers of ethanol-induced liver injury. We review the mechanisms by which alcohol injures hepatocytes and the response of hepatic sinusoidal cells to alcohol-induced injury. We also discuss how recent insights into the pathogenesis of ALD will affect treatment and management of patients.

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Invariant natural killer T cells contribute to chronic-plus-binge ethanol-mediated liver injury by promoting hepatic neutrophil infiltration

Cited by 74 publications

References 39 publications

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Aging aggravates alcoholic liver injury and fibrosis in mice by downregulating sirtuin 1 expression

Natural killer T cells in liver injury, inflammation and cancer

Linking Pathogenic Mechanisms of Alcoholic Liver Disease With Clinical Phenotypes

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